title: Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate.
abstract: Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic. Among the seven eukaryotic phosphoinositides the best studied species is phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits. No phosphatidylinositol other than PI(4,5)P2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by phosphatidylinositol-3-phosphates(PI(3)P). How phosphatidylinositol conversion from PI(4,5)P2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) by class II phosphatidylinositol-3-kinase C2α (PI(3)K C2α) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P2 or PI(3)K C2α impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P2 by PI(3)K C2α is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P2 in endocytosis and unravel a novel discrete function of PI(3,4)P2 in a central cell physiological process.
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie & Freie Universität Berlin, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
authors.forename: York
authors.initials: Y
authors.lastname: Posor
authors.forename: Marielle
authors.initials: M
authors.lastname: Eichhorn-Gruenig
authors.forename: Dmytro
authors.initials: D
authors.lastname: Puchkov
authors.forename: Johannes
authors.initials: J
authors.lastname: Schöneberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Ullrich
authors.forename: André
authors.initials: A
authors.lastname: Lampe
authors.forename: Rainer
authors.initials: R
authors.lastname: Müller
authors.forename: Sirus
authors.initials: S
authors.lastname: Zarbakhsh
authors.forename: Federico
authors.initials: F
authors.lastname: Gulluni
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Michael
authors.initials: M
authors.lastname: Krauss
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
authors.forename: Jan
authors.initials: J
authors.lastname: Schmoranzer
authors.forename: Frank
authors.initials: F
authors.lastname: Noé
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D058541:Class II Phosphatidylinositol 3-Kinases / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D058305:Sorting Nexins / Q000378:metabolism; D013997:Time Factors
chemical_list: D018129:Phosphatidylinositol Phosphates; C400533:SNX9 protein, human; D058305:Sorting Nexins; C060980:phosphatidylinositol 3,4-diphosphate; D058541:Class II Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase